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Mutations in RP1L1, a retina-specific doublecortin (DC) domain protein, cause inherited retinal disorders including occult macular dystrophy (OMD), yet the underlying mechanisms remain poorly defined. Here, we show that the RP1L1 R45W variant, prevalent in East Asian individuals with OMD, confers a toxic gain-of-function phenotype characterized by abnormally strong MT binding. Live-cell imaging revealed an approximately twofold increase in MT association relative to wild-type RP1L1. Molecular dynamics simulations indicated that R45W stabilizes RP1L1\u2013\u03b1-tubulin interactions via cation\u2013\u03c0 contacts and reduced electrostatic repulsion. Remarkably, low concentrations of glycerol selectively disrupted these aberrant interactions, restoring MT binding to wild-type levels in both cellular and biochemical contexts. Our study elucidates a structural and mechanistic basis for RP1L1 R45W hyper-binding and demonstrates that small-molecule modulation of DC-domain interactions might provide a variant-specific therapeutic strategy for RP1L1-related retinopathies.<\/jats:p>","DOI":"10.1242\/jcs.264447","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T08:07:46Z","timestamp":1768896466000},"source":"Crossref","is-referenced-by-count":1,"title":["Hyperactive microtubule binding of RP1L1 R45W underlies retinal degeneration and is suppressed by glycerol"],"prefix":"10.1242","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7517-000X","authenticated-orcid":false,"given":"Yuqi","family":"Ye","sequence":"first","affiliation":[{"name":"State Key Laboratory of Membrane Biology 1 , Tsinghua\u2013Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, McGovern Institute for Brain Research, MOE Key Laboratory for Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengyang","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology 1 , Tsinghua\u2013Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, McGovern Institute for Brain Research, MOE Key Laboratory for Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology 2 , School of Basic Medical Sciences, Tsinghua University, Beijing 100084 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaiming","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology 1 , Tsinghua\u2013Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, McGovern Institute for Brain Research, MOE Key Laboratory for Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangshuo","family":"Ou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology 1 , Tsinghua\u2013Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, McGovern Institute for Brain Research, MOE Key Laboratory for Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"2026021103304831900_JCS264447C1","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1016\/j.ajhg.2010.08.009","article-title":"Dominant mutations in RP1L1 are responsible for occult macular dystrophy","volume":"87","author":"Akahori","year":"2010","journal-title":"Am. 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